JPH0225422A - Sensory function loss inhibitor - Google Patents

Abstract

PURPOSE: To obtain a depressant which is composed of a benzazepine type calcium channel blocker alone or in combination with an ACE depressant and suppresses the loss of perceptional function (it contains memorization ability) of mammals for a long period of time. CONSTITUTION: This depressant for loss of perceptional function is composed of a benzazepine type calcium channel blocker, e.g. diltiazem, a compound of the formula (R1 is H, an alkyl, an alkanoyl, an arylcarbonyl, etc.; R and R3 are each H, an alkyl, a cycloalkyl, etc., or are incorporated together with the nitrogen binded with them to form pyrrolidinyl and piperidinyl; R4 and R5 are each H, a halogen, an alkyl, an aryloxy, OH, CN, etc.; (n) is 2 and 3) alone or in combination of the compound with an angiotensin converting enzyme(ACE) depressant, e.g. a substituted proline derivative and a carboxyalkyldipeptide derivative. The medicine is useful for the treatment of vascular dementia such as initial denatured dementia caused in the senile and presenile generations and arteriosclerotic dementia or for the delay of the progress of the disease.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to inhibitors of loss of sensory function, more particularly benzazepine type calcium duct blockers such as diltiazem, SQ317.65 or SQ32324 alone or in combination with captopril, zofenopril, fosinopril or S
Angiotensin converting enzyme inhibitors such as Q29852 (
The long-term administration of sensory function loss inhibitors consisting of a combination of A and CE inhibitors (hereinafter abbreviated as CE inhibitors) to mammals may result in various types of dementia in the mammals, such as Alzheimer's disease. It relates to methods for suppressing the loss of sensory functions (including memory) that occur with or without disease.

The present invention provides a drug used in the above-mentioned method for suppressing loss, and the drug is composed of a benzazepine-type calcium duct blocker alone or a combination of this and an ACE inhibitor,
By administering a therapeutically effective amount of the therapeutically effective amount to a mammal over a long period of time systemically, e.g., orally or parenterally, to suppress the loss of sensory function during the administration period, the long-term sensory function of the mammal can be improved. For example, it may be possible to inhibit loss of memory, attention, concentration and knowledge) or to treat or slow the progression of Alzheimer's disease or other dementias.

In the present invention, when a calcium duct blocker and an ACE inhibitor are used in combination, the ratio of the calcium duct blocker to the ACE inhibitor is
The weight ratio of the CE inhibitor may be selected within a range of about 0[1 to 10:1, preferably about 0.4:1 to 2.5:1.

The calcium duct blocker (hereinafter sometimes referred to as calcium entry blocker or calcium antagonist) used in the present invention is diltiazem, which is described in U.S. Patent No. 35622.57, that is, formula: % formula % ) [(5H)-one is preferred.

Furthermore, as a calcium tube blocker, U.S. Patent No. 47
Examples include benzazepine derivatives of the formula: (CH2)n N /\2R3 or pharmaceutically acceptable salts thereof, as described in No. 48239.

In the above formula, R1 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl or -
C-NXlX2; R2 and R3 are each independently hydrogen, alkyl, cycloalkyl or arylalkyl, or R2 and R
3 is combined with the nitrogen atom to which they are bonded to form pyrrolidinyl,
piperidinyl or molbonyl; R4 and R5 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, diarylalkoxy, arylalkyl, cyan, hydroxy, alkanoyloxy, -0-C-NX
IX2, fluoro-substituted alkoxy, fluoro-substituted alkyl, (cycloalkyl)alkoxy, -NO2, -NX
3X4, -8(O)m alkyl, -8(O)m aryl, OO]111 -C-X5 or 10-C-X6; n is 2''! or 3; m is 0, 1 or 2; X engineering and X2 each independently represent hydrogen, alkyl,
Aryl or heteroaryl, or Xe and X2
are combined with the nitrogen atom to which they are bonded to form pyrrolidinyl,
Piperidinyl or morpholinyl; X3 and X4
each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl or -C-NXIX2; X5 is hydroxy, alkoxy, aryloxy,
amine, alkylamino or dialkylamino; and X6 is alkyl, alkoxy or aryloxy, and when R4 is a 7-alkyl group, R4 must have a tertiary carbon atom attached to the ring.

Furthermore, in the various terms used above, "aryl" refers to phenyl and substituted phenyl. Specific examples of substituted phenyl include 1.2 or 3 amines, alkylamino, dialkylamino, nitro, halogen, hydroxyl, trifluoromethyl, alkyl (1 to 4 carbon atoms), alkoxy (1 to 4 carbon atoms), It is phenyl substituted with alkanoyloxy, carbamoyl or carboxyl group.

"Heteroaryl" refers to pyridininopepyrolyl, imidazolyl, furinopechenyl or thiazolyl.

Such a benzazepine derivative has the formula: [wherein R
2 and R3 are both CH3, or one of R2 and R3 is H and the other is CH3], or a hydrochloride thereof is preferred.

The drug of the present invention can be used to treat early degenerative dementia (
For example, it is useful for treating or slowing the progression of Alzheimer's disease, Pick's disease, and Pinswangaard's disease) and for treating or slowing the progression of vascular dementias such as atherosclerotic dementia (including multiple infarct dementia and Pinswangaard's disease).

Examples of the ACE inhibitor used in the present invention include substituted proline derivatives (captopril, i.e., 1-
((2S)-3-mercapto-2-methylpropionyl)-L-proline is preferred], U, S, Patent No. 437
4829 (enalapril, i.e., N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-
7'Ojn is preferred).

Other specific examples of ACE inhibitors suitable for use in the present invention include phosphonate-substituted amino acids or imino acids or their salts ((S)-1-46-amino 2-[Hydroxy(4
-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline [preferably SQ29852], U, S, phosphinylalkanoylprolines disclosed in Patent No. 4168267 (preferably fosinopril), substituted proline mercaptoacyl derivatives (zofenopril is preferred), U.S., Patent No. 4337
Examples include phosphinylalkanoyl-substituted prolines disclosed in U.S. Patent No. 201, and phosphonamidates disclosed in U.S. Pat.

Furthermore, as specific examples of ACE inhibitors that can be used in the present invention, Beecham's BRL36378, CA, 102 Near 2588v and Jap, J-Pharmacol, disclosed in European Patent Nos. 80822 and 60668,
40: 373 (1986), Ciba Geigy's CG51482 [(J, 3
-((1-ethoxycarbonyl-3-phenyl-(IS
)-propylcoamino)-2,3,4,5-tetrahydro-2-okine-1-(3S)-benzazepine-1-
acetic acid/HC6) and the company's CGS 16617 (i.e., 3
(S) -[C(Is)-5-amino-1-carboxypentyl]amine)-2,3,4,5-tetrahydro-
2-oxo-IH-1-benzazepine-1-ethanoic acid], Eur.

Therap, Res, 39:671 (1986) and 40:543 (1986), cetapril (alacepril from Dainirapon), European Patent No. 79
-022 and Curr, Ther, Res, 4
0 Ramipril (Hoechst) disclosed in (1986), Arzneimittelforschung
35: 1254 (1985).
70 (Hoechst) J, CarcHovasc, P
Cilazapril (Hoffmann-La-Rotssier), FE, disclosed in Pharmacol, 9: 39 (1987).
BS Lett, 165:201 (1984);
Curr, Therap, Res, 37:34
2 (1985) and European Patent Application No. 12-40
Dinopril (Merck & Co.) disclosed in No. 1, Intrapril (Delapril) disclosed in U.S. Patent No. 4385051, Cl1n, Exp, Pharmacol.

Physiol, 10: 131 (1983) (Fentiafryl, Santen), J. Cardiovasc, Pharma.
col, 5: 6 4 3, 6 5 5
(1983), Intrapril (Schering), Acta, Pharmacol, Toxi
Spirapril (Schering), disclosed in Eur, J.
, Cl1n, Pharmacol.

3 [Verindopril (Celpia) disclosed in 519 (1987), Quinapril (Warner-Lambert) disclosed in U.S. Patent No. 4344949, Pharmac.
ogist 26: 243, 266 (19
CI 925 (Warner Lambert Company) disclosed in 84) (i.e., [3S-[2(R(')R(town)]3
R(machi)-2-42-[1-(ethoxycarbonyl)-
J,
Med, Chem, 26:394 (1983)
includes WY-44221 (WY-S Co., Ltd.) disclosed in .

When carrying out the present invention, the above-mentioned calcium duct blocker alone or in combination with an ACE inhibitor may be administered to mammals (e.g., monkeys, dogs, cats, rats, humans, etc.), and the calcium duct blocker itself may be administered as a tablet or tablet. It can be formulated in conventional systemic dosage forms such as capsules, elixirs or injection solutions. Such dosage forms may also contain the necessary carrier materials, excipients, lubricants, buffers, antibacterial agents, fillers (such as mannitrile), antioxidants (such as ascorbic acid or bisulfite), etc. May be blended.

Although oral dosage forms are preferred, parenteral dosage forms are also quite satisfactory.

The dose to be administered should be carefully adjusted according to the age, weight and symptoms of the patient, as well as the method of administration, dosage form, lifestyle and intended effects.

That is, to obtain satisfactory results in the case of oral administration, the calcium duct blocker is used alone in an amount of about 0.01 to 100 cycles/kQ, more preferably about 0.1 to 25 cycles/kQ, or About 0.01~100■/kq, preferably about 0.01~
It may be used in combination with an ACE inhibitor of 25 kQ/kQ, and when used in combination, the calcium duct blocker and the ACE inhibitor may be mixed in the same oral dosage form, or
Alternatively, they may be administered simultaneously in separate oral dosage forms.

Preferred oral dosage forms (e.g. tablets or capsules) have a dosage of about 0.1 to 500 µm, preferably about 125 to 200 µm.
(more preferably about 25 to 150 μ) of a calcium tube blocker alone, or about 1 to 350 μ;
Preferably about 2 to 200 cm (more preferably about 30 to
150 IQ) in combination with an ACE inhibitor.

For parenteral administration, the calcium duct blocker is used alone at about 0.005-10/kQ, preferably about 0.01-1/kQ, or about 0.01005-20/kQ.
It may be used in combination with Q, preferably about 0.01-2~/kq of ACE inhibitor.

The pharmaceutical composition of the invention may be administered once or twice a day in the above-mentioned dosage form.
Can be administered in ~4 divided doses. It is recommended that patients start administration at a low dose and then gradually increase the dose.

Tablets of various sizes may be prepared containing one or both of the active substances in the above dosage ranges, for example with a total weight of about 50 to 70 mg.
011117 tablets, the remaining ingredients being physiologically acceptable carrier materials used in normal pharmaceutical practice.

Liquid formulations can also be prepared by dissolving or suspending one or both of the active substances in a conventional pharmaceutically acceptable liquid vehicle to give the desired dosage of 1 to 4 spoonfuls.

Such dosage forms can be administered to patients on a regimen of 1 to 4 doses per day.

According to other modifications, both active substances may be administered separately in individual dosage units, at the same time or at carefully adjusted times, in order to more closely control the dosing schedule.

The simultaneous presence of both active substances gives the same result, as the blood is increased and maintained on a regular dosing schedule. The individual active substances can be formulated individually in different unit dosage forms in the same manner as described above.

Particularly in tablets or capsules for oral administration, it is more convenient and preferable to mix the calcium duct blocker and the ACE inhibitor in quantitative amounts.

When preparing the pharmaceutical compositions of the invention, the active substances in the amounts described above may be combined in individual dosage unit forms with physiologically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavoring agents, etc. etc., and can be formulated according to normal pharmaceutical practice.

Specific examples of adjuvants that can be incorporated into the tablets include binders such as gum tragacanth, gum acacia, cornstarch or gelatin, excipients such as calcium phosphate or cellulose, disintegrants such as cornstarch, potato starch, and alginic acid, and Stair J. lubricants such as phosphoric acid or magnesium stearate, sweetening agents such as sucrose, lactose or saccharin, and flavoring agents such as orange, peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain, in addition to the auxiliary ingredients mentioned above, a liquid carrier such as a fatty oil. In addition, other substances may be added to improve the physical properties of the coating or unit dosage form. For example, tablets or capsules may be coated with shellac or sugar or both. Cirozzo's elixirs contain the active substance, water as a carrier, such as alcohol, glycerol as a solubilizing agent, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring agent such as cherry or orange.

Many of the active substances mentioned above generally form known pharmaceutically acceptable salts, such as alkali metal salts and other conventional basic salts or acid addition salts. The basic substances used in the formation of such salts are those known which substantially correspond to the sharp compounds.

The preparations thus prepared are administered over a long period of time, ie, as long as the signs of loss of sensory function remain or the symptoms of loss persist.

It is also possible to use sustained release formulations, which allow for the administration of a fixed amount of the formulation twice a week, once a week, or monthly. Note that an administration period of at least 1 to 2 weeks is required to obtain the minimum pharmacological effect.

The following examples are preferred embodiments of the invention.

Example 1 A diltiazem formulation suitable for oral administration for suppressing loss of sensory function is shown below.

1000 tablets, each containing 100 μm of diltiazem, are prepared from the following ingredients:

Diltiazem・・・・・・・・・1
00g cornstarch ・・・・・・・・・
・・・ 50g gelatin ・・・・・・
...7.5g Avicel (microcrystalline cellulose)...
・・・・・・・・・ 25g Magnesium stearate
...... 2.5 g of the above diltiazem and cornstarch are mixed with an aqueous gelatin solution. The mixture is dried and ground to a fine powder. Add Avicel, then Magnesium Stearate, mix and granulate. This is then compressed into tablets using a tablet molding machine to produce 1000 tablets for suppressing loss of sensory function, each containing 100 μg of active ingredient.
get pieces.

Example 2 10 tablets each containing 200 μ of SQ32324
00 pieces are manufactured from the following ingredients.

Component y(d-
cis)-3-(acetyloxy)-1,3゜45-tetrahydro-4-(4-methoxyphenyl)-1-[2
-(Methylamino)ethyl]-6-() IJ fluoromethyl)-2H-1-benzazepin-2-one monohydrochloride (SQ32324)
...Mountain...200 lactose
・・・・・・・・・100 Abyssel
・・・・・・・・・150 Corn starch ・・・－・・・・・・ 50 Magnesium stearate ・・・・・・・・・ 5
The above SQ32324, lactose and Avicel are mixed, and cornstarch is blended therein. Add magnesium stearate. The dry mixture is compressed in a tablet machine to give 1000 tablets (505 sq.) each containing 200 sq. of active ingredient. Such tablets,
A methyl cellulose (Meth, ocel E 15 ) solution containing yellow g6-containing lake as a coloring agent is coated. The resulting tablets are useful in inhibiting loss of sensory function.

Example 3 Two-piece #1 gelatin capsules each containing 250 to 250 g of diltiazem are filled with the following ingredient mixture.

Ingredients ■Diltiazem 250
Magnesium stearate ·········
7USP Lactose・・・・・・
-193 The resulting capsules are useful in inhibiting loss of sensory function.

Example 4 An injection solution used for suppressing loss of sensory function is produced according to the following procedure.

(d-cis)-3-(acetyloxy)-1-[(2-
dimethylamino)ethyl)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one monohydrochloride (SQ31765)
・・・・・・・・・500 tamethylparaben
・・・・・・・・・ 5■Propylparaben ・・・・・・・・・ 1 mg Sodium chloride ・・・・・・・・・ 25
．． 9 Water for injection (qs,) ・・・・・・
...5e Above SQ31765, preservative and chloride) Dissolve IJum in 31 parts of water for injection, then make up to 51 volume with water for injection. The solution is filtered through a sterile filter, filled aseptically into sterile vials, and sealed with sterile rubber stoppers. Each vial contains 5 mQ of injection solution at a concentration of 100 μ active ingredient/mQ.

Example 5 Captopril as a sensory loss inhibitor suitable for oral administration
Diltiazem formulations are shown below.

100 mg each of 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline and 1
1000 tablets containing 00 m'l of diltiazem are prepared from the following ingredients:

1- [, (2S)-3-mercapto-2-methylpropionyl)-L-proline (captopril)...
...100g Diltiazem ...1
00,9' Cornstarch ・River...
・・・ 50! q Gelatin...
7.5.7 Avicel (microcrystalline cellulose)
・・・・・・・・・ 25I Magnesium Stearate ・・・・・・・・・ 2.5g Captopril above,
Mix diltiazem and corn starch with aqueous gelatin solution. The mixture is dried and ground to a fine powder. Add Avicel, then Magnesium Stearate, mix and granulate. This is compressed into tablets using a tablet molding machine.
1000 tablets for inhibiting loss of sensory function, each containing 200 to 200 active ingredients, are obtained.

Example 6 In Example 5, 1-(3-
In the same manner, except that mercapto-2-D-methylpropanoyl)-L-proline was used, 1 of 100 μl of each
-(3-mercapto-2D-methylpropanoyl)-L
- Manufacture 1000 tablets for inhibiting loss of sensory function containing proline and 100 μm of diltiazem.

Example 7 SQ29852 and 200 g of 200 g each
1000 tablets containing SQ32324 are manufactured from the following ingredients:

Ingredients gSQ2
9852 ・・・・・・・・・ 200
SQ32324・・・・・・・・・
200 lactose・・・・・・
・100 Abyssel...
・・・ 150 Cornstarch ・・・
・・・・・・・・・ 50 Magnesium stearate
・・・・・・・・・ 5 Above SQ29852. SQ
32324, Lacquer and Avicel, and blend this with cornstarch. Add magnesium stearate. The dry mixture was compressed in a tablet machine into 1000 tablets each containing 200 μl of active ingredient.
tablets (505"li') are obtained. In such tablets,
Coat with a methyl cellulose (Methocel E 15 ) solution containing Yellow #6 containing lake as a colorant. The resulting tablets are useful in inhibiting loss of sensory function.

Example 8 An injection solution for use in the treatment or prevention of loss of sensory function is produced according to the following procedure.

S Q 29852 ...== 5
001JI9 Diltiazem...
...300 mQ methylparaben
・・・・・・・・・ 5g propylparaben
・・・・・・・・・ly Sodium chloride
・・・・・・・・・ 25.7 Water for injection (q
s, ) 51 Dissolve the above SQ 29852, diltiazem, preservative and 1-IJium chloride in 31 parts of water for injection, then make up to 54 volumes with water for injection. Filter the solution through a sterile filter.
Aseptically fill it into a sterile vial and seal it with a sterile rubber stopper. Each vial contains 5 mfl of injection solution of 100 μl of active ingredient/-concentration.

Example 9 In Example 5, N-(1-
Ethoxycarbonyl-3-phenylpropizu)-l-
Tablets for inhibiting loss of sensory function are produced in the same manner except that alanyl-proline (Enalapriva) is used and SQ32324 is used in place of diltiazem.

Example 10 A tablet for suppressing loss of sensory function is produced in the same manner as in Example 5, except that zofenopril is used instead of captopril.

Example 11 A tablet for suppressing loss of sensory function is produced in the same manner as in Example 5, except that Honnobriva is used instead of captopril.

Example 12 In Example 5, S in place of captopril.

Tablets for suppressing loss of sensory function are produced in the same manner except that Q29852 is used.

Example 13 In order to demonstrate the effectiveness of a benzazepine-type calcium tract blocker alone or in combination with an ACE inhibitor in suppressing loss of sensory function, the following experiment is conducted.

Male Sprauge-Dawley
(25 weeks old, weight 350-400)
g) were housed in isolation in stainless steel cages with constant access to food and water and maintained at a constant room temperature of 22-24°C with each 12 hour light/dark cycle. All tests were conducted for approximately 6 hours in the dark component of a light-dark cycle and were performed in a standard shuttle box apparatus (L
high Valley Electronics
#146-04] in a dimly lit, soundproof room using a Plexiglas room (50 x 20 x 20 m) divided by a central barrier of height 70 m.

The conditioned stimulus consisted of a 10-second tone emanating from a 5onlert placed at the midpoint of the ceiling of the laboratory. Constant current Schottker scrambler (Le
high valley electronics
#133-33) to apply a floor current of 0.8 mA.

The day before each rat's training begins, the laboratory is surveyed for 10 minutes without any sounds or shocks. The day of laboratory research is followed by 15 days of training. Each rat received 20 doses per day on a variable schedule with 30 second intervals.
Receive multiple attempts.

During the training period, the shock can be extinguished by back-and-forth movement of the central barrier from one side to the other during a 10 second tonal period without any medical treatment. During this period, if the rat does not cross the central barrier, the tone remains until the rat escapes to the other half of the laboratory.
Adds floor shock. Rats that consistently remain in the central barrier are excluded from the experiment. An automatic counter records the number of avoidance responses, escapes, and crossings between trials, and a running timemeter records the total shock time for each rat.

A total of 99 rats passed the acceptance criterion and these Test for disappearance of conditioned avoidance response (CAE) for 14 days. These rats were randomly assigned to receive captopril (ACE inhibitor) (10M4/# and 30#/#), zofenopril (ACE inhibitor) (10■/kQ and 30■/kq).
], fosinopril (ACE inhibitor) (10~/kq and 30~/kq), methyldopa (no ACE inhibitory activity) (10/kq and 30~/kQ), shrimp captopril (a derivative of captopril, with ACE inhibitory activity) The test groups to be administered are 9 mice, respectively. All were freshly prepared and administered i.p. (volume 1/m2) 2 days and 1 hour before the test.
Q) Yes. The test consists of the same 20 trials per day as described above, except that the shock is discontinued if the rat ceases to make reciprocating movements (shuttle action) during the 10 second tone period.

Completely stop the tone and proceed with the test.

Two-way analysis of variation in CAE data yields important overall differences in the rate of shuttlecock disappearance among treatment groups.

From the above experimental results, diltiazem and ACE inhibitors (i.e., fosinopril, zofenopril, and captopril) have a protective effect on memory for previously learned tasks, whereas diltiazem and ACE inhibitors, such as shrimp captopril and methyldopa, which do not have ACE inhibitory activity, It is observed that the compound has no protective effect against memory loss of previously learned tasks.

It will also be appreciated that all of the active compounds and combination formulations used in the present invention can be used to treat or slow the progression of Alzheimer's disease.

In addition, calcium duct blockers may be used, such as benzazepine derivatives (e.g., SQ3
2324 and SQ31765).

Example 14 In order to demonstrate the efficacy of diltiazem in improving sensory acuity and sensory impairment, the following experiment was conducted.

Experimental method regarding the ability to improve basic behavior and the ability to antagonize scopolamine damage in a mouse behavior test An experiment was conducted according to the procedure using a black:white test box described below. Male Alpino (BKW) mice (initial weight 25-30.p) were used.

Mice were housed in groups of 10 in housing cages and provided with food and water ad libitum. Mice were kept under a 12-hour light/dark cycle, with lights turned off at 8 a.m. and lights on at 8 p.m.

The test box is a box with an open top (45 x 2
7 X 27 cyn), 40% of the area is painted black and illuminated with dark red light (60WX1), the other area is painted white, and white light (60WX1) is illuminated from a position 1.7 cyn above the box. It consists of a brightly lit light and a bright light. Is the access between these two areas the floor in the center of the partition (which also helps prevent light spreading between the two compartments of the test box)? Opening provided at the bell position (7,5X
7.5c7n). 9α in the floor area
Draw a square line.

Habitual testing was performed daily by placing the mouse in the center of the white section of the test box (mice were transferred from a dark housing environment in a dimly lit container to a laboratory room where lighting was maintained with low red light; aversion to bright white conditions)
. The test was conducted between 8:30pm and 12:30pm. The test time was 5 minutes per day. Mouse behavior was determined by remote video recording and the following measurements were made.

1. Latency time (seconds) to move from the white area to the black area 2. Number of trailing searches in the white and black areas during the 5 minutes of the test 3. Number of times the line was crossed (exploratory walking movements) in the white and black areas during the 5 minutes of the test 4. Eggplant stays in the black part of the box for 1-5 minutes 5.
Number of transfers between the black and white parts of the test box during eggplant 1-5 min (this parameter does not change in any situation of this experiment, so we omit displaying data on transfers and further comments) In general, animals As they become familiar with the test system, they move into the black part of the box, and behavioral exploration is indicated by trailing exploration and crossing the line. Scopolamine was administered at 0.25mf//kQ・1 to disrupt the habit pattern.
．． It was used at a dose of p. Disruption is achieved by a single dose of scopolamine that disrupts the learning pattern on the day of treatment, with subsequent reinstatement, or by continued daily treatment with scopolamine 1 hour before testing. The dose of scopolamine was carefully selected within a range that did not cause autonomic neuropathy (0.257 v/kQ-i, p; trimethylscopolamine had no effect on behavior). 0.2
5 Under the action of scopolamine, the mouse advances to the partition door, explores the opening,
The headache passes through the body, but this has no relation to the dim environment and escapes from the bright aversive environment.

Results A normal learning curve for mice in the habit test is a decrease in the number of backward movements and line crossings in the white compartment, an increase in the number of backward movements in the black compartment, a decrease in latency to move to the black compartment, and an increase in the time spent in the black compartment. 5-6 days, as evidenced by the percentage. Acute administration of scopolamine caused lesions in control mice. In the example data for trailing back, mice learned to avoid the white aversive environment, and on day 6, they performed most of this behavior in the black area, but this was prevented by the scopolamine lesion, and the white aversive environment The activity in the black part increased, and the activity in the black part decreased. This damage caused by scopolamine could be prevented by arecoline. Selection of the dose and route of arecoline is important to avoid undesirable autonomic dysfunction.
It was given continuously by intraperitoneal injection from an Alzet osmotic minipump at a dose of kQ/day. It is interesting to note that although continuous treatment with this dose of arecoline suppresses the scopolamine impairment of habit, the basal learning or the time course of habit is not affected by the administration of arecoline. This contrasts with the findings for diltiazem.

Using procedures similar to those described above, control mice and mice treated with diltiazem were subjected to behavioral manipulation on days 6 and 1.
Day 00: Challenged with scopolamine. First, treatment with diltiazem was found to promote basic learning operations. Second, treatment with diltiazem completely antagonized the damage caused by scopolamine.

To evaluate the potential of hydergine to improve sensory function in a mouse behavioral test, the same test records described for arecoline and diltiazem were used. Hydergine was obtained off-the-shelf and administered orally to mice at the human dose once daily (test) 60 minutes prior to treatment. Treatment with hydergine was clearly observed to enhance learning performance in mouse behavioral tests.

The number of backward movements in the white area rapidly decreased, but the number of backward movements in the black area increased accordingly. In addition, the number of crossings in the white area decreased to below the control value on the second day of the test, whereas it increased in the black area, and the rate of increase (%) in the time spent in the black area was remarkable on the second day, On days 2, 3 and 4, the latency time for movement from the white area to the black area decreased.

Treatment with hydergine is not accompanied by latent psychological anxiety, and its dosage is limited to 0.1 x 1 tcq-p daily.
o, was maintained at a constant amount. After 4 days, a small number of mice developed some motor deficits and sedation, which particularly affected locomotion latencies from the white environment, so data from such a small number of mice had to be excluded from the analytical experiments.

A very important point is that hydergine (similar to diltiazem but in contrast to arecoline) can enhance basic learning but cannot antagonize the effects of scopolamine, which is detrimental to performance, but in any case After that, the change in the number of steps back, the change in the number of line crossings or the percentage change in the time spent in the black area, and the latency time to leave the white aversive environment were measured. The lack of any effect) contrasts with the pronounced antagonistic effects of arecoline and diltiazem.

In another series of experiments, mice were habituated for 10 days and challenged daily with 0.25-/kq scopolamine.

Habits were impaired during scopolamine challenge. After scopolamine-induced damage was observed, mice were treated with scopolamine and daily with arecoline (50 ~/kq/day, intraperitoneal injection from Alzet's osmotic minipump),
Alternatively, giving diltiazem completely prevented scopolamine injury.

Conclusion Regarding the evaluation of perceptual ability and the ability to improve perceptual impairment: Using a mouse behavior test, mice are repeatedly placed in the white compartment of a white:black test box.

As mice are repeatedly exposed to this test situation, they avoid the aversive white parts of the brightly lit environment, rush to the black parts, spend more time there, and make the most exploratory steps and line crossings. Learn to show.

Habit (learning) time is 5-6 days. This basal learning time is unaffected by arecoline (50 μ/kQ day, administered by continuous intraperitoneal injection, dose and route chosen to avoid undesirable autonomic effects). However, this dose of arecoline is able to successfully antagonize the behavioral disturbances caused by acute challenge with scopolamine (0.25 μ/kLj·i, p, ). The dose of scopolamine should also be taken with caution to avoid excessive peripheral autonomic neuropathy, and in particular to avoid visual effects that could affect test behavior, i.e., a lack of visual effects as confirmed by visual observation and measurements of pupillary function. selected. Methylscopolamine at a dose of 0.25''9/kQ·1.p does not affect mouse behavior.

The effects of scopolamine are obvious. In other words, mice that have learned to avoid the white environment will not try to enter the black area even if they can easily find the entrance (except for a short period of time), and will suddenly retreat to the black area and avoid the white environment. is blocked by scopolamine treatment.

Unlike arecoline, treatment with low doses of diltiazem increases the rate of habit. Diltiazem was found to antagonize the impairment of habitual behavior caused by acute challenge with scopolamine.

Heide J Regi 7 (0, I M!; l/kQ-1], 0
-11 times a day) increases the speed of habitual processes, similar to diltiazem (in this respect, arecoline does not).
However, hydergine treatment does not affect the behavioral disturbances caused by acute challenge with scopolamine (this contrasts with the effects of both diltiazem and cholinergic agents).

In another experiment, after 10 days of behavioral testing, animals were given continuous impairment by administering scopolamino daily for up to 14 days.

This persistent impairment caused by scopolamine can be antagonized by arecoline (50 μ/kQ/day, intraperitoneal injection) and diltiazem.

Patent Applicant: E.R. Squibb & Sons, Inc.

Claims (1)

[Scope of Claims] 1. An agent for suppressing long-term loss of sensory function in mammals, characterized by comprising a benzazepine-type calcium tract blocker alone or in combination with an angiotensin-converting enzyme inhibitor. 2. The agent for suppressing loss of sensory function according to claim 1, wherein the calcium duct blocker is diltiazem. 3. Calcium tube blocker has a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or ▲There are mathematical formulas, chemical formulas, tables, etc. ▼; R_2 and R_3 are each independently hydrogen, alkyl, cycloalkyl, or arylalkyl, or R_
2 and R_3 together with the nitrogen atom to which they are bonded are pyrrolidinyl, piperidinyl, or morpholinyl; R_4 and R_5 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, diarylalkoxy, arylalkyl,
Cyano, hydroxy, alkanoyloxy, ▲Mathematical formulas, chemical formulas, tables, etc.▼, fluoro-substituted alkoxy, fluoro-substituted alkyl, (cycloalkyl)alkoxy,
-NO_2, -NX_3X_4, -S(O)_m alkyl, -S(O)_m aryl, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; n is 2 or 3; m is 0, 1 or 2; X_1 and X_2 are each independently hydrogen, alkyl, aryl or heteroaryl, or X_1 and X
_2 together with the nitrogen atom to which they are bonded form pyrrolidinyl, piperidinyl or morpholinyl, X_3 and X_
4 are each independently hydrogen, alkyl, alkanoyl,
Arylcarbonyl, heteroarylcarbonyl or When a 7-alkyl group, R_4 must have a tertiary carbon atom attached to the ring. The above aryl refers to phenyl and substituted phenyl (
1, 2 or 3 amino, alkylamino, dialkylamino, nitro, halogen, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkanoyloxy, carbamoyl or carboxyl as a substituent; ), and heteroaryl refers to pyridinyl, pyrrolyl, imidazolyl, furyl, thienyl or thiazolyl] or a pharmaceutically acceptable salt thereof. Loss inhibitor. 4. The calcium duct blocker is (d-cis)-3-(acetyloxy)-1-[(2-dimethylamino)ethyl]
-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-
Benzazepine-2-one monohydrochloride [SQ3176
5] or (d-cis)-3-(acetyloxy)-1
,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-[2-(methylamino)ethyl]-6-(
trifluoromethyl)-2H-1-benzazepine-2
The agent for suppressing loss of sensory function according to claim 1, which is monohydrochloride [SQ32324]. 5. The angiotensin converting enzyme inhibitor according to claim 1, wherein the angiotensin converting enzyme inhibitor is a phosphonate-substituted amino acid or imino acid or a salt thereof, a substituted proline derivative, a carboxyalkyl dipeptide derivative, a phosphinylalkanoylproline derivative, or a phosphonamidate derivative. Agent for suppressing loss of sensory function. 6. The agent for inhibiting loss of sensory function according to claim 1, wherein the angiotensin converting enzyme inhibitor is a substituted proline derivative. 7. The agent for inhibiting loss of sensory function according to claim 1, wherein the angiotensin converting enzyme inhibitor is a carboxyalkyl dipeptide derivative. 8. The agent for inhibiting loss of sensory function according to claim 1, wherein the angiotensin converting enzyme inhibitor is a phosphinylalkanoylproline derivative. 9. The agent for inhibiting loss of sensory function according to claim 1, wherein the angiotensin converting enzyme inhibitor is a phosphonamidate derivative. 10. The agent for inhibiting loss of sensory function according to claim 1, wherein the angiotensin-converting enzyme inhibitor is a phosphonate-substituted amino acid or imino acid, or a salt thereof. 11. The angiotensin converting enzyme inhibitor is captopril, enalapril, 1-[N-[hydroxy(4-phenylbutyl)phosphinyl]-2-alanyl]-L-proline or a salt thereof, SQ29852, zofenopril, fosinopril, or (S )-1-[6-amino-
The agent for suppressing loss of sensory function according to claim 1, which is 2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-proline. 12. The calcium duct blocker is diltiazem, (d-cis)-3-(acetyloxy)-1-[(2-dimethylamino)ethyl]-1,3,4,5-tetrahydro-4
-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one monohydrochloride [SQ31765], or (d-cis)-3-(acetyloxy)-1,3 ,4,5-tetrahydro-4-
(4-methoxyphenyl)-1-[2-(methylamino)ethyl]-6-(trifluoromethyl)-2H-1-
Benzazepine-2-one monohydrochloride [SQ3232
4], and the dosage is approximately 0.4 times per day.
1 to 500 mg, the angiotensin converting enzyme inhibitor that may be present is captopril, and the dosage is 1 to 500 mg per day.
The agent for inhibiting loss of sensory function according to claim 1, which is about 0.1 to 500 mg in ~4 doses. 13. An agent for treating or delaying the progression of Alzheimer's disease in mammals, which comprises a benzazepine-type calcium tract blocker alone or a combination thereof with an angiotensin-converting enzyme inhibitor. 14. The calcium duct blocker is diltiazem, (d-cis)-3-(acetyloxy)-1-[(2-dimethylamino)ethyl]-1,3,4,5-tetrahydro-4
-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one monohydrochloride [SQ31765] or (d-cis)-3-(acetyloxy)-1,3, 4,5-tetrahydro-4-(
4-methoxyphenyl)-1-[2-(methylamino)
Ethyl]-6-(trifluoromethyl)-2H-1-benzazepin-2-one monohydrochloride [SQ32324
] and the angiotensin converting enzyme inhibitor that may be present is captopril, SQ29852, zofenopril, fosinopril, enalapril, or (S)-1-[
6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl-L-
The agent for treating or delaying the progression of Alzheimer's disease according to claim 13, which is proline.